Dynamically-Crosslinked Self-Assembled Thermoresponsive

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Dynamically-Crosslinked Self-Assembled Thermoresponsive Microgels with Homogeneous Internal Structures Eva Mueller, Richard J. Alsop, Andrea Scotti, Markus Bleuel, Maikel C. Rheinstadter, Walter Richtering, and Todd Hoare Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b03664 • Publication Date (Web): 20 Dec 2017 Downloaded from http://pubs.acs.org on December 20, 2017

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Dynamically-Crosslinked Self-Assembled Thermoresponsive Microgels with Homogeneous Internal Structures Eva Mueller1, Richard J. Alsop2, Andrea Scotti3, Markus Bleuel4, Maikel C. Rheinstädter2, Walter Richtering3, Todd Hoare*1 1

Department of Chemical Engineering, McMaster University, 1280 Main St. W, Hamilton,

Ontario, Canada L8S 4L7 2

Department of Physics and Astronomy, McMaster University, 1280 Main St. W, Hamilton,

Ontario, Canada L8S 4M1 3

Department of Physical Chemistry (IPC), RWTH Aachen, Landoltweg 2, 52074 Aachen,

Germany 4

Neutron-Condensed Matter Science Group, National Institute of Standards and Technology

(NIST), 100 Bureau Drive, Gaithersburg, Maryland 20899, United States; Department of Materials Science and Engineering, University of Maryland, College Park, MD 20742-2115

* To whom correspondence should be addressed E-mail: [email protected]

ACS Paragon Plus Environment

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Abstract The internal morphology of temperature-responsive degradable poly(N-isopropylacrylamide) (PNIPAM) microgels formed via an aqueous self-assembly process based on hydrazide and aldehyde-functionalized PNIPAM oligomers is investigated. A combination of surface force measurements, small angle neutron scattering (SANS), and ultra-small angle neutron scattering (USANS) was used to demonstrate that the self-assembled microgels have a homogenously cross-linked internal structure. This result is surprising given the sequential addition process used to fabricate the microgels, which was expected to result in a densely crosslinked shell-diffuse core structure. The homogeneous internal structure identified is also significantly different than conventional microgels prepared via precipitation polymerization, which typically exhibit a diffuse shell-dense core structure. The homogenous structure is hypothesized to result from the dynamic nature of the hydrazone crosslinking chemistry used coupled with the assembly conditions chosen that promote polymer interdiffusion. The lack of an internal crosslinking gradient within these degradable and monodisperse microgels is expected to facilitate more consistent drug release over time, improved optical properties, and other potential application benefits.


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Introduction Microgels, colloidal networks of crosslinked water-soluble polymers with dimensions < 1 µm, have been demonstrated to be useful materials in a wide range of biomedical and environmental applications. In particular, temperature-responsive microgels and nanogels based on poly(Nisopropylacrylamide) (PNIPAM) have attracted significant research interest due to their ability to change their diameter1-4, hydrophobicity5, pore size6, and surface charge7-8 as a function of temperature, the so-called volume phase transition temperature (VPTT) behavior. These thermally switchable properties have been applied in drug delivery9 (to target locally hotter areas in the body, such as poorly vascularized but quickly metabolizing cancerous sites10-11), bioseparations12-13 (to reversibly adsorb/desorb a target molecule), membranes14-15 (to open or close pores), nanoswitches16 (to oscillate on/off responses in microfluidic channels), and other applications4, 17. Each of these applications works due to some combination of the reduced hydrophilicity and/or the reduced pore size observed upon heating, with the former governing the strength of interactions between the microgel and more hydrophobic molecules18-19 and the latter governing the diffusivity of molecules through the gel network20.

The swelling properties and the transition temperature responses of microgels are governed by not only the chemistry but also the internal microgel structure. The internal structure regulates the speed/degree of swelling21-23, the breadth of the volume phase transition (less internally heterogeneous particles have narrower transitions)24-25, the rate of intraparticle diffusion26, the ease of microgel functionalization27 and the capacity of the microgels for the uptake/release of small molecules6, 28. The internal structure of microgels is most commonly studied using smallangle neutron scattering (SANS) in dilute suspensions, although static light scattering can also


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give some insight29. Direct modeling expressions for the scattering intensity distribution have been developed to describe structural changes induced by changes in temperature30-32, crosslinking density33, or particle size29-30 as well as inherent compositional gradients resulting from the synthetic conditions used (e.g. batch, semi batch or controlled monomer feed)34.

The internal structure of microgels is directly related to the method by which the microgels are synthesized. Conventional PNIPAM microgels are made by a precipitation polymerization process35 in which NIPAM monomers are polymerized with N,N’-methylenebisacrylamide (MBA) crosslinker using a water-soluble free radical initiator (i.e. potassium sulfate) at a temperature above the lower critical solution temperature (LCST) of PNIPAM to drive particle formation24, 36. Other monomers may be copolymerized to obtain microgels with desired properties and the process may be carried out in batch, semi-batch or continuous modes24. The resulting microstructure of the microgels produced using this conventional technique has been shown to relate directly to the copolymerization ratios between the constituent monomers and crosslinkers used to prepare the microgel37. For example, since the MBA crosslinker typically used to prepare microgels reacts faster than NIPAM, the core of the resulting microgel is more densely cross-linked than the shell, resulting in a “fuzzy sphere” nanostructure1. The fuzzy sphere internal structure of conventional PNIPAM microgels was further studied and formally quantified with a small angle neutron scattering (SANS) model by Stieger et al.30 Additionally, Geisel et al. investigated and indirectly confirmed the core-corona structure of PNIPAMcopolymerized with methacrylic acid (MAA) microgels using interface/surface force measurements38. This inhomogeneous structure makes the prediction of drug binding18, swelling responses39, and other key microgel properties challenging, although also offering opportunities to leverage these structures in specific applications (e.g. bioconjugation3).


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Given that copolymerization kinetics govern the microgel morphology via precipitation polymerization, it is possible to manipulate the feed rate of the monomers/crosslinkers within the scope of the conventional precipitation process to create uniformly crosslinked particles. For example, Acciaro et al. have prepared homogeneous PNIPAM microgels by using a continuous reactor to maintain the concentrations of monomer and cross-linker constant21, Du’s group copolymerized an unprotected catechol monomer that could self-crosslink to create a more homogeneous internal structure40, and we have demonstrated the capacity to create uniform functional group distributions in microgels using semi-batch delivery of the functional monomer41. In all cases, the homogenously cross-linked or functionalized microgels showed significantly different optical and swelling properties relative to conventional batch polymerized microgels, showing the importance of controlling and understanding the internal morphology of microgels in designing particles for applications.

Alternately, to avoid the dominance of free radical copolymerization kinetics on the morphology of the resulting microgels, two-step microgel fabrication techniques have been reported in which a pre-formed PNIPAM polymer or oligomer is heated above its LCST to form a nanoaggregate followed by crosslinking to stabilize that aggregate into a microgel. Multiple post-crosslinking strategies including UV irradiation42-43 and self-condensation of pendant methoxysilyl groups44 have been reported to create microgels from the nanoaggregates, with the distribution of crosslinking sites governed by UV light penetration and/or the surface activity of the precursor polymer(s) in the former case and the self-association of the hydrophobic methoxysilyl groups in the latter case.


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However, particularly in the context of biological applications, controlling degradability remains a challenge with both the conventional synthesis approach as well as these nanoaggregation stabilization strategies. In the former case, there is no direct way to control the molecular weight of degradation products (even if degradable crosslinkers are used) to ensure the ultimate clearance of the materials; in the latter case, the bonds formed are non-degradable. Alternate methods such as pre-polymer crosslinking inside inverse emulsions allows for both homogeneous internal morphologies as well as degradation into well-defined products45; however, this approach typically results in non-uniform particle size distributions46. Microfluidics can be utilized to produce more uniform microgels with specific flow-focusing techniques47 but typically results in larger particle sizes in the micron size range instead of the nanoscale.

Recently, we have developed a novel method to create degradable and monodisperse microgels using a thermally-driven self-assembly approach mimicking the conventional microgel fabrication process but using well-defined hydrazide and aldehyde-functionalized PNIPAM oligomers instead of the monomers as the building blocks. Mixing the hydrazide (PNIPAM-Hzd) and aldehyde (PNIPAM-Ald)-functionalized oligomers results in the formation of degradable hydrazone crosslinks2; by maintaining the molecular weight of those oligomers below the kidney clearance limit, we can facilitate renal clearance of the synthetic polymer-based microgel network following degradation of the hydrazone crosslinks. These degradable analogues of conventional thermoresponsive microgels can be fabricated rapidly (VPTT, the dynamic crosslinking chemistry may permit interdiffusion of the added polymer into the gel structure over time (as observed with the polyelectrolyte LbL assemblies49) despite the fast and multidentate covalent crosslinking anticipated between the added functional polymer and residual surface or near-surface complementary functional groups.

Herein, we investigate the internal morphology of these self-assembled PNIPAM microgels, with or without subsequent LbL modification, using a combination of surface force measurements, small angle neutron scattering (SANS), and ultra-small angle neutron scattering (USANS). In contrast to our initial hypothesis about the structure of these oligomeric self-assembled microgels, both Langmuir trough experiments and SANS/USANS (both on the microgels as a whole as well as contrast matched SANS highlighting the individual distributions of PNIPAMHzd and PNIPAM-Ald) indicate that the self-assembled microgels feature highly uniform internal morphologies, a result we attribute to the dynamic instead of static nature of the hydrazone crosslinks formed. As such, the oligomeric self-assembly approach not only leads to degradable microgels but also highly homogeneous microgel structures which may be of significant benefit in optical, drug delivery, and other applications in which uniform crosslink densities should yield more uniform properties.

Experimental Section Materials: N-isopropylacrylamide (NIPAM, 99%), acrylic acid (AA, 99%), thioglycolic acid (98%), aminoacetaldehyde dimethyl acetal (99%), sodium cyanoborohyride (95%), 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO, 98%), and methacryloyl chloride (purum) were


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purchased from Sigma Aldrich (Oakville, Canada). NIPAM was purified by dissolving 1 g/mL in toluene at 60°C, adding a 2:3 ratio of hexane to toluene, placing the solution in an ice bath for 12 hours, filtering/rinsing with hexanes, and drying the recrystallized NIPAM monomer under N2 overnight. Adipic acid dihydrazide (ADH, Alfa Aesar, 98%), N’-ethyl-N-(3dimethylaminopropyl)-carbodiimide (EDC, Carbosynth, Compton CA, commercial grade), 2,2azobisisobutryic acid dimethyl ester (AIBMe, Wako Chemicals, 98.5%), and ethanol (Commercial Alcohols, Brampton, Ontario) were purchased and used without further purification. Milli-Q grade distilled deionized water (DIW) was used for all experiments. Deuterium oxide (99.9 atom% D) was purchased from Sigma Aldrich (Oakville, Canada) for use in neutron scattering experiments. N-decane (Sigma Aldrich, 99%) was purchased and triplecolumned with aluminum oxide prior to use.

Prepolymer Synthesis: Hydrazide-functionalized (PNIPAM-Hzd) and aldehyde-functionalized (PNIPAM-Ald) pre-polymers were synthesized using the previously reported protocols2. Briefly, PNIPAM-Hzd was prepared via free radical copolymerization of NIPAM (4.5 g) and acrylic acid (0.5 g) in 20 mL of ethanol using thioglycolic acid (TGA, 80 µL) as the chain transfer agent and 2,2-azobisisobutyric acid dimethyl ester (AIBME, 0.056 g) as the initiator (reaction temperature = 60°C). Gel permeation chromatography (GPC) using a Waters 590 HPLC pump, three Waters Styragel columns (HR2, HR3, HR4; 30 cm x 7.8 mm (ID); 5 µm particles) at 40°C, a Waters 410 refractive index detector operating at 35 °C, and DMF as the solvent indicated that the resulting polymer had a molecular weight of 21.6 kDa, while base-into-acid conductometric titration indicated a stoichiometric incorporation of acrylic acid (~15 mol%) into the polymer. Subsequently, the acrylic acid residues were conjugated using carbodiimide chemistry with a 5-


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fold excess of adipic acid dihydrazide, resulting in an overall conversion of 95% of acrylic acid residues to hydrazide functionalities (i.e. ~14 mol% of the total monomer residues were functionalized with a hydrazide group). Deuterated PNIPAM-Hzd (d-PNIPAM-Hzd) was similarly prepared by substituting NIPAM with d7-PNIPAM (Polymer Source, Montreal, PQ) in the recipe, with base-into-acid conductometric titration indicating the same stoichiometric (~15 mol% total monomer) incorporation of acrylic acid into the polymer and ~95% conversion of those acrylic acid residues into hydrazide groups following carbodiimide coupling.

PNIPAM-Ald was prepared by copolymerizing NIPAM (4.5 g) with N-(2,2dimethoxyethyl)methacrylamide53 (DMEMAm, 0.95 g) using the same polymerization conditions used for the hydrazide polymer, resulting in a polymer with a molecular weight of ~15.1 kDa via GPC. Subsequently, acid hydrolysis of the pendant acetal groups in DMEMAm into aldehyde groups was performed by dissolving the initial polymer in 1 M HCl and hydrolyzing over 24 hours, resulting in 12 mol% of total monomer residues in the polymer bearing aldehyde groups. All polymers were dialyzed against Milli-Q water for 6 cycles of at least 6 hours and lyophilized for storage.

Microgel Particle Size Measurements: Dynamic light scattering measurements were performed using a Brookhaven 90Plus particle analyzer running Particle Solutions Software (Version 2.6, Brookhaven Instruments Corporation), using a 659 nm laser and a 90 degree detection angle. Each measurement was performed at a count rate between 200-500 kilocounts/s for 2 minutes and repeated at least six times. The intensity-weighted particle sizes and polydispersities were


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reported as averages of these six replicate measurements, with the reported error representing the standard deviation of these replicates.

Microgel Fabrication: Oligomer self-assembled microgels were prepared following our previously reported self-assembly/precipitation protocol (Figure 1)2. Both PNIPAM-Hzd and PNIPAM-Ald were dissolved at 1 wt% in D2O or a mixture of D2O/H2O appropriate for index matching (see the SANS section for details on how this ratio was chosen). The PNIPAM-Hzd solution (5 mL) was then heated to a temperature above its lower critical solution temperature (LCST) to create stable nanoaggregates, after which the PNIPAM-Ald solution was added dropwise (~1-2 drops per second) at either 5 or 20% mass PNIPAM-Ald/mass of PNIPAM-Hzd to stabilize the nanoaggregate via a hydrolytically-labile hydrazone bond. All self-assemblies were performed at a reaction temperature of 70°C, well above the LCST of PNIPAM-Hzd (~56°C) to ensure efficient nanoaggregate formation. The mixture was magnetically stirred (350 RPM) at 70°C for 15 minutes following PNIPAM-Ald addition to ensure crosslinking prior to cooling.

PNIPAM-Ald cannot diffuse Fixed crosslinking Core-shell structure

PNIPAM-Ald can diffuse Fixed crosslinking

T>LCST Mixing & Addition of PNIPAM-Ald PNIPAM-Hzd

Uncrosslinked Nanoaggregate

Gradient crosslink structure PNIPAM-Ald can diffuse Dynamic crosslinking Uniform structure

Figure 1: Schematic of precipitation/self-assembly process used to fabricate degradable microgels from functional PNIPAM oligomers and anticipated structures of resulting microgels depending on the diffusibility of the PNIPAM-Ald crosslinker and the permanence of the crosslinks formed. The homogeneous morphology is consistent with the structural characterization results.


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To assess the impact of adding additional functional polymer following the initial assembly process (i.e. “layer-by-layer” self-assembly), the pre-formed microgel suspensions were cooled overnight and then re-heated to 70°C. Either PNIPAM-Hzd or PNIPAM-Ald at a concentration of 5 or 20% mass/mass of initial PNIPAM-Hzd was then added as described above for the initial PNIPAM-Ald crosslinking step, with the process repeated as desired to add additional “layers” to the assembly.

Small-Angle Neutron Scattering (SANS): SANS experiments were conducted using the 30 m SANS NGB30 at the NIST Center for Neutron Research (NCNR, Gaithersburg, MD). Sampleto-detector distances of 1, 4 and 13 m were used in conjunction with neutrons of wavelength 6 Ǻ, while the lens geometry was also used at the 13 m detector distance with 8.4 Ǻ wavelength neutrons to expand the accessible q range. The microgels were self-assembled in D2O as described in the previous section and loaded into NCNR’s custom titanium/quartz sample holders (diameter 19 mm and path length 2 mm) without further dilution. The internal gap thickness of the sample cell was 2 mm, which corresponds to ~800 L of test solution. Three microgels were assessed at four temperatures (25, 32, 37 and 45°C) spanning the volume phase transition temperature (VPTT) of PNIPAM-based microgels: (1) 0.05 Ald:Hzd microgels (prepared with a 1 wt% PNIPAM-Hzd starting solution), (2) 0.20 Ald:Hzd microgels (1 wt% PNIPAM-Hzd starting solution) and (3) 0.05 Ald:Hzd microgels (2 wt% PNIPAM-Hzd starting solution). In addition, four layer-by-layer microgels were assembled in the sequences listed below and measured at 25°C only to assess the mass distribution in each microgel as a result of the layer-by-layer assembly process: (1) 0.05 Ald:Hzd microgel + PNIPAM-Hzd, (2) 0.05


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Ald:Hzd microgel + PNIPAM-Ald, (3) 0.05 Ald:Hzd microgel + PNIPAM-Hzd + PNIPAM-Hzd and (4) 0.05 Ald:Hzd microgel + PNIPAM-Hzd + PNIPAM-Ald. Note that each “+ Polymer” addition step listed above involves cooling the sample overnight, re-heating to the assembly temperature of 70°C, and adding the next polymer in sequence at the concentrations listed above. Additional measurements were also performed on PNIPAM-Hzd precursor polymer solutions at the same concentration and temperature used for microgel self-assembly, allowing for direct correlation between the structure of the nanoaggregate before and after crosslinking. The low q range data were acquired by counting for ~20 min using the 13 m distance, the medium q range data were acquired by counting for ~15 min using the 4 m distance, and the high q range data were acquired for ~5 min using the 1 m detection distance. The three ranges were merged using the DAVE on-site data reduction tool and standard Igor Pro macros54-55.

The contrast matching experiment on the self-assembled PNIPAM microgels was performed by fabricating microgels using d7-PNIPAM-Hzd as the seed polymer and (hydrogenated) PNIPAMAld as the crosslinking polymer (0.2 Hzd:Ald polymer mass ratio), with the ratio of D2O:H2O in the suspending solvent changed in order to match one of the two constituent polymers. The match points were first calculated based on the atomic composition to predict the theoretical scattering length density for each of the polymers, corresponding to theoretical match points 67:33 (v:v) D2O:H2O for d7-PNIPAM-Hzd and 21:79 (v:v) D2O:H2O for hydrogenated PNIPAM-Ald. These values were refined by conducting scattering experiments both at the calculated match point as well as ±10% solvent mixtures from this calculated match point, with the experimental D2O:H2O ratio producing zero scattering determined by regression to be 63:37 D2O:H2O for d7-PNIPAM-Hzd and 22:78 D2O:H2O for PNIPAM-Ald. Microgels were then


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self-assembled as described in the previous section in the matched solvents to ensure the total microgel concentration was constant for each experiment. SANS experiments were conducted as previously described for the non-contrast matched samples.

Ultra-small Angle Neutron Scattering (USANS): USANS experiments were conducted on the contrast-matched microgels using the BT5 USANS at the NIST Center for Neutron Research (NCNR, Gaithersburg, MD)56. The neutron wavelength used was 2.4 Ǻ ± 6%, with the q range spanning between ~0.00003 Ǻ-1 to 0.002 Ǻ-1 to slightly overlap the lower end of the accessible q range from SANS (0.001 Ǻ-1) and allow for efficient stitching/scaling of the data using the DAVE on-site data reduction tool. Samples were loaded into the same sample holder used for SANS analysis.

Neutron Scattering Data Analyses: The SANS analysis on the bulk microgels and the contrastmatched microgels was done using Interactive Data Language (IDL) and Igor Pro, using the fuzzy sphere model shown in Equation [1].

= where =

∆ 〈 〉 + + !" 1 + ∗ *3456778 (9 #$%&'()*()+,(exp 2 ().

:

; ∗?

@

[1]

E

sin D F

Note that the brackets denote an average over the size distribution, where 〈 〉 represents the form factor G, is the structure factor (for dilute solutions, S(q) = 1 for all q), is the correlation length (roughly representing the mesh size of the gel network), HIJKKL denotes the width of the smeared or “fuzzy” particle surface (which, when set to 0, reduces the expression to


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that of a homogeneous sphere), m is the Lorentzian exponent, and q is the scattering vector, related to the neutron wavelength (M and the scattering angle (N. Since the instrument resolution causes a smearing of the data, the intrinsic desmearing function in IgorPro (the convolution of P(q) with a Gaussian function) was used to account for smearing effects57.

Langmuir Trough: Compression isotherms were recorded and analyzed on the oil-water interface using a KSV-NIMA Langmuir trough with two barriers operating at a speed of 108 mm/min and a platinum Wilhelmy plate to measure the change in interfacial tension from the clean interface to the interface covered with microgel particles. Distilled water (200 mL) was used as the aqueous phase and triple-columned n-decane (200 mL) was used as the oil phase. Low crosslink ratio (0.05 Ald:Hzd polymer mass ratio) or high crosslink ratio (0.20 Ald:Hzd polymer mass ratio) self-assembled microgels were dispersed in the aqueous phase. As the particles were compressed, the change in interfacial tension was measured with the platinum Wilhelmy plate, with the measurement converted to a surface pressure using the KSV-NIMA software.

Results Microgel Particle Size: The hydrodynamic radius and polydispersity of the microgels in a dilute suspension of D2O, the layer-by-layer assembled microgels in D2O, and the contrast-matched microgels at the relevant D2O:H2O ratios used for the contrast matching experiments at 25°C (T

Dynamically-Crosslinked Self-Assembled Thermoresponsive

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